Mutations causing the degeneration of specific nerve cells have been identified in many organisms. We have identified and cloned two genes that can be mutated to cause the degenerative and late-onset death of specific nerve cells in the nematode Caenorhabditis elegans. Dominant mutations in the gene mec-4 lead to the deaths of all six of the C. elegans touch receptor neurons, whereas a dominant mutation in the gene deg-1 results in a similar appearing death of a small set of different neurons. Molecular analysis reveals that both genes are members of the same gene family. We are calling the products of this family "degenerins." Suppression studies have identified the gene mec-6 as being required for the degenerations and, thus, begin to define components needed for this abnormal cell death. The proposed research will use these and other mutations to study the process of this inherited neurodegeneration in C. elegans and the nature of the degenerins and their suppressors. The specific aims of the research are: 1. to continue the molecular characterization of the deg-1 and mec-4 genes and their products; 2. to characterize molecularly the mec-6 gene; 3. to characterize the events occurring during cell degeneration in these mutants using light and electron microscopy; 4. to identify and characterize molecularly other members of the degenerin gene family in C. elegans; and 5. to identify other genes that are required for the degenerations. The health relatedness of this project stems from the nature of the mutations. We do not know whether degenerins are found in higher organisms (although crosshybridization is seen) or whether, if found, they are involved in specific disease situations. Nonetheless, the study of these genes using molecular and transmission genetics and observations on single, identified cells should highlight cell biological processes underlying inherited degenerative neurological disorders.